Narcolepsy is now considered a neurodegenerative disorder and as with other diseases where CNS neurons die it is necessary to explore new strategies to transfer genes to restore function. Here we propose developing a gene transfer approach that will serve as a neurobiological tool to understand the networking underlying narcolepsy and also to ultimately reverse symptoms. We have created a replication-defective HSV-1 amplicon vector to transfer the gene for mouse preprohypocretin together with reporter genes into hypocretin null mice. Our very strong preliminary data shows abundant and robust expression of hypocretin in the lateral hypothalamus of hypocretin null mice along with unambiguous decline of narcoleptic symptoms. We are proposing an integrated series of in vitro and in vivo aims that will serve as a foundation for a more comprehensive effort to utilize the gene transfer approach to reverse the symptoms of narcolepsy in hypocretin null mice. Appropriate experiments with controls are proposed to strengthen the conclusions. Here, we are focusing on transferring the gene for mouse preprohypocretin because this neuropeptide can be easily identified using simple immunohistochemical procedures. We will then migrate to transferring the gene for the receptor, a much more difficult task since there is no good antibody that will allow for verification of the gene transfer. Our overall strategic intent is to transfer the gene for the hypocretin 2 receptor in canine narcolepsy, thereby replacing a mutated receptor gene with a healthy one. PUBLIC HEALTH RELEVANCE Narcolepsy is now considered a neurodegenerative disorder and it is necessary to explore new strategies to treat the disease. The significance of this project is that it will develop a gene transfer approach that will serve as a neurobiological tool to understand the networking underlying narcolepsy and also to ultimately restore some function.